The FDA’s recent call for public input (https://www.regulations.gov/document/FDA-2024-N-2980-0001), which included industry leaders such as Merck and Novartis on host cell protein (HCP) immunogenicity, has sparked a wave of industry feedback and a clear consensus is emerging: generic total HCP ELISA kits in many cases are outdated.

Key Takeaways:

• Limited Coverage: Generic kits detect only 40–60% of HCPs, missing critical proteins such as PLBL2.
• Protein Specific Risks: Individual HCPs can trigger immune responses even at trace levels.
• Orthogonal Testing: Combining ELISA with LC-MS/MS and in-silico tools is now best practice.
• Regulatory Alignment: FDA and industry leaders are shifting to risk-based, protein-specific control.

"Across biopharma and regulatory commentary—from Merck and Novartis to EpiVax and AAM, leaders agree that

the industry must move beyond generic total HCP assays. Protein-specific ELISAs, validated with orthogonal LC-

MS/MS and in-silico risk models, offer the precision and confidence needed to identify and control high-risk HCPs,

ensuring safer biologics, better comparability, and stronger regulatory alignment.”

1) Limited Coverage

• Commercial ELISA Kits: detect only 40–60% of host cell proteins. Novartis reports platform assays reach ~60%, while process-specific ELISAs achieve 80–90% coverage. OFA confirms commercial kits offer just ~40% coverage.
• Method-Dependent Results: Nadine Ritter explains that ELISA quantification is not comparable across products, which makes generic kits unreliable for regulatory or comparability studies.
• Missed Immunogenic Proteins: EpiVax shows that LC-MS/MS identifies critical HCPs—like PLBL2—that generic ELISAs miss.

Key Message: Platform ELISAs lack the coverage and specificity needed to ensure patient safety. Only protein-specific ELISAs can accurately quantify and monitor high-risk HCPs.

2) Protein-Specific Risk

• Industry Leaders Agree: identifying individual HCPs is essential for risk management.
• Orthogonal Testing is Best Practice: Merck, Novartis, AAM, and EpiVax all use ELISA + LC-MS/MS to verify HCP clearance and identify specific contaminants.
  Immunogenicity Profiling: EpiVax’s tools (EpiMatrix, JanusMatrix, ISPRI-HCP) pinpoint proteins like PLBL2 that pose immunogenic or adjuvant risks.
• Assay Sensitivity: AAM and OFA highlight that total HCP methods lack dynamic range, while LC-MS/MS provides resolution to detect trace-level risks.

Key Message: The future of HCP control lies in protein-specific detection, not in total-HCP quantification

3) Orthogonal Testing

• Multi-Modal Testing: Merck, Novartis, AAM, OFA, and EpiVax all advocate combining ELISA, LC-MS/MS, and computational tools.
• Predictive Power: EpiVax’s ISPRI-HCP platform and Merck’s LC-MS verification show that multi-modal characterization outperforms generic ELISA kits.

Key Message: Regulators and innovators agree that orthogonal + computational assays are the new gold standard.

4) Regulatory Alignment

• Outdated Guidance: AAM, OFA, and Merck call for FDA updates to reflect modern tools like LC-MS/MS and in-silico modeling.
• Nonclinical Pathways: AAM proposes that clinical immunogenicity studies may be unnecessary if HCPs are properly characterized.
• Process-Specific Validation: Experts agree that total ppm values are not comparable, protein-specific assays are required.

Key Message: The regulatory framework is evolving toward protein-specific, risk-based control—and your analytics should too.

ICL’s protein-specific HCP ELISA kits are built for this new era offering targeted detection, regulatory confidence, and enhanced patient safety.

ICL's Host Cell Protein ELISA Solutions

We offer a full line of CHO-specific Host Cell Protein ELISA kits for targeted HCP detection which can be found here: 
Host Cell Protein Solutions

High-Impact HCP Targets Include:

• PLBL2 – Known to be immunogenic and to degrade adjuvants
• NUCB2 – Implicated in stress response and calcium regulation
• CTSA, LPLA2, Clusterin, MMP-19 – Other key CHO-associated proteins often missed by generic assays

Our HCP ELISA Kits Feature:

• Highly specific sandwich-format design, with minimal sample-matrix interference
• CHO-derived standards for accurate quantification
• Fast turnaround times (typically under 3 hours)
• Detection sensitivity suitable for process development and QA/QC